CNS-Specific Regulatory CD8+ T Cells in Autoimmune Demyelination

描述(申请人提供)：多发性硬化症(MS)是一种炎症性、脱髓鞘的中枢神经系统(CNS)疾病。我们对多发性硬化症的免疫学过程的大量了解来自对其自身免疫性动物模型-实验性自身免疫性脑脊髓炎(EAE)的研究。然而，绝大多数关于EAE和MS的研究集中在评估和靶向CD4+T细胞应答上，一般假设这些疾病主要是由Th1/Th17和Th2/Treg调节的。最近的研究表明，CD8+T细胞在自身免疫性脱髓鞘的发病机制和调节机制中可能起重要作用。CD8+T细胞在自身免疫病理过程中的作用一直没有得到充分的研究，也存在争议。虽然已知CD8+T细胞是MS病变中的主要T细胞，并且在病理部位以寡克隆性方式扩增，但这些细胞的抗原特异性及其作用尚不清楚。在MS患者和多种EAE模型中，CNS特异性CD8+T细胞的发生率很高。虽然直观地认为CNS靶向、MHC I类限制的CD8+T细胞反应可能在疾病中起致病作用，但我们最近的研究首次证明了神经抗原特异性CD8+T细胞在EAE中具有新的和意想不到的免疫抑制作用。因此，我们假设在自身免疫性脱髓鞘疾病过程中，中枢神经系统特异性CD8+T细胞形成一支重要的内源性免疫调节臂。我们认为，这一自然过程可以被利用来开发有效的免疫治疗策略。本申请中提出的实验将直接解决CNS反应性CD8+T细胞的免疫调节机制，描述它们的细胞、分子和运输需求。此外，将定义这一群体中最有效的免疫抑制亚群，目标是开发一种新的免疫治疗方法。我们相信，拟议的实验将为健康和疾病过程中CD8+T细胞介导的免疫调节提供更基本的见解，并将为这种疾病和其他免疫中介疾病的新干预策略铺平道路。 公共卫生相关性：实验性自身免疫性脑脊髓炎(EAE)是人类免疫介导性疾病多发性硬化症(MS)的小鼠模型。在这种疾病的背景下，我们发现了中枢神经系统靶向CD8+免疫细胞的新的免疫抑制作用。在拟议的研究中，我们将剖析这种抑制的机制，目的是为这种疾病开发创新的治疗策略，并对被忽视的MS免疫学领域提供重要的见解。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). A great deal of our understanding about the immunologic processes that underlie MS derives from studies in its autoimmune animal model, experimental autoimmune encephalomyelitis (EAE). However, the vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses, with the general assumption that these diseases are predominantly Th1/Th17-mediated and Th2/Treg-modulated. Recent reports from others and us indicate that CD8+ T cells may play an important role in the pathogenesis as well as regulation of autoimmune demyelination. The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. While it is known that CD8+ T cells represent the predominant T cell in an MS lesion and are oligoclonally expanded at the site of pathology, the antigenic specificity of these cells and their role is not known. There is high prevalence of CNS-specific CD8+ T cells in MS patients as well as multiple models of EAE. While it makes intuitive sense that a CNS-targeted, MHC Class I-restricted CD8+ T cell response would likely have a pathogenic role in disease, our recent studies have generated the first evidence for a novel and unexpected immune suppressor role for neuroantigen-specific CD8+ T cells in EAE. We thus hypothesize that CNS-specific CD8+ T cells form an important arm of intrinsic immune regulation during autoimmune demyelinating disease. We propose that this natural process can be harnessed for the development of an effective immunotherapeutic strategy. The experiments proposed in this application will directly address the mechanisms of immune modulation by CNS-reactive CD8+ T cells, delineating their cellular, molecular and trafficking requirements. Moreover, the most potent immune suppressive subset of this population will be defined with the goal of developing a novel immunotherapeutic approach. We believe that the proposed experiments will provide greater fundamental insight into CD8+ T cell-mediated immune regulation during health and disease and will pave the way for newer intervention strategies for this and other immune-mediated diseases. PUBLIC HEALTH RELEVANCE: Experimental autoimmune encephalomyelitis (EAE) is a mouse model for the human immune-mediated disease multiple sclerosis (MS). We have found a novel immune suppressive role for central nervous system- targeted CD8+ immune cells in the context of this disease. In the proposed studies, we will dissect the mechanisms of such suppression with the goal of developing innovative treatment strategies for this disease and providing important insights into an overlooked area of MS immunology.